This invention relates to compounds of formula I, which may be useful for treating diseases or conditions caused by or exacerbated by histamine-3 receptor activity, pharmaceutical compositions containing compounds of formula I and methods of treatment using compounds of formula I.
Histamine is a well-known mediator in hypersensitive reactions (e.g. allergies, hay fever, and asthma) which are commonly treated with antagonists of histamine or xe2x80x9cantihistamines.xe2x80x9d It has also been established that histamine receptors exist in at least two distinct types, referred to as H1 and H2 receptors.
A third histamine receptor (H3 receptor) is believed to play a role in neurotransmission in the central nervous system, where the H3 receptor is thought to be disposed presynaptically on histaminergic nerve endings (Nature, 302, 832-837 (1983)). The existence of the H3 receptor has been confirmed by the development of selective H3 receptor agonists and antagonists (Nature, 327, 117-123 (1987)) and has subsequently been shown to regulate the release of other neurotransmitters in both the central nervous system and peripheral organs, particularly the lungs, cardiovascular system and gastrointestinal tract.
A number of diseases or conditions may be treated with histamine-3 receptor ligands wherein the H3 ligand may be an antagonist, agonist or partially agonist, see: (Imamura et al., Circ.Res., (1996) 78, 475-481); (Imamura et. al., Circ.Res., (1996) 78, 863-869); (Lin et al., Brain Res. (1990) 523, 325-330); (Monti et al., Neuropsychopharmacology (1996) 15, 31-35); (Sakai, et al., Life Sci. (1991) 48, 2397-2404); (Mazurkiewicz-Kwilecki and Nsonwah, Can. J. Physiol. Pharmacol. (1989) 67, 75-78); (Panula, P. et al., Neuroscience (1998) 44, 465-481); (Wada et al., Trends in Neuroscience (1991) 14, 415); (Monti et al., Eur. J. Pharmacol. (1991) 205, 283); (Mazurkiewicz-Kwilecki and Nsonwah, Can. J. Physiol. Pharmacol. (1989) 67, 75-78); (Haas et al., Behav. Brain Res. (1995) 66, 41-44); (De Almeida and Izquierdo, Arch. Int. Pharmacodyn. (1986) 283, 193-198); (Kamei et al., Psychopharmacology (1990) 102, 312-318); (Kamei and Sakata, Jpn. J. Pharmacol. (1991) 57, 437-482); (Schwartz et al., Psychopharmacology; The fourth Generation of Progress. Bloom and Kupfer (eds). Raven Press, New York, (1995) 397); (Shaywitz et al., Psychopharmacology (1984) 82, 73-77); (Dumery and Blozovski, Exp. Brain Res. (1987) 67, 61-69); (Tedford et al., J. Pharmacol. Exp. Ther. (1995) 275, 598-604); (Tedford et al., Soc. Neurosci. Abstr. (1996) 22, 22); (Yokoyama et al., Eur. J. Pharmacol. (1993) 234, 129); (Yokoyama and Iinuma, CNS Drugs (1996) 5, 321); (Onodera et al., Prog. Neurobiol. (1994) 42, 685); (Leurs and Timmerman, Prog. Drug Res. (1992) 39, 127); (The Histamine H3 Receptor, Leurs and Timmerman (eds), Elsevier Science, Amsterdam, The Netherlands (1998); (Leurs et al., Trends in Pharm. Sci. (1998) 19, 177-183); (Phillips et al., Annual Reports in Medicinal Chemistry (1998) 33, 31-40); (Matsubara et al., Eur. J. Pharmacol. (1992) 224, 145); (Rouleau et al., J. Pharmacol. Exp. Ther. (1997) 281, 1085); (Adam Szelag, xe2x80x9cRole of histamine H3-receptors in the proliferation of neoplastic cells in vitroxe2x80x9d, Med. Sci. Monit., 4(5): 747-755, (1998)); (Fitzsimons, C., H. Duran, F. Labombarda, B. Molinari and E. Rivera, xe2x80x9cHistamine receptors signalling in epidermal tumor cell lines with H-ras gene alterationsxe2x80x9d, Inflammation Res., 47 (Suppl 1): S50-S51, (1998)); (R. Leurs, R. C. Vollinga and H. Timmerman, xe2x80x9cThe medicinal chemistry and therapeutic potentials of ligand of the histamine H3 receptorxe2x80x9d, Progress in Drug Research 45: 170-165, (1995)); (R. Levi and N. C. E. Smith, xe2x80x9cHistamine H3-receptors: A new frontier in myocardial ischemiaxe2x80x9d, J. Pharm. Exp. Ther., 292: 825-830, (2000)); (Hatta, E., K Yasuda and R. Levi, xe2x80x9cActivation of histamine H3 receptors inhibits carrier-mediated norepinephrine release in a human model of protracted myocradial ischemiaxe2x80x9d, J. Pharm. Exp. Ther., 283: 494-500, (1997); (H. Yokoyama and K. linuma, xe2x80x9cHistamine and Seizures: Implications for the treatment of epilepsyxe2x80x9d, CNS Drugs, 5(5); 321-330, (1995)); (K. Hurukami, H. Yokoyama, K. Onodera, K. Iinuma and T. Watanabe, AQ-0145, xe2x80x9cA newly developed histamine H3 antagonist, decreased seizure susceptibility of eletrically induced convulsions in micexe2x80x9d, Meth. Find. Exp. Clin. Pharmacol., 17(C): 70-73, (1995); (Delaunois A., Gustin P., Garbarg M., and Ansay M., xe2x80x9cModulation of acetylcholine, capsaicin and substance P effects by histamine H3 receptors in isolated perfused rabbit lungsxe2x80x9d, European Journal of Pharmacology 277(2-3):243-250, (1995)); and (Dimitriadou, et al., xe2x80x9cFunctional relationship between mast cells and C-sensitive nerve fibres evidenced by histamine H3-receptor modulation in rat lung and spleenxe2x80x9d, Clinical Science. 87(2):151-163, (1994). Such diseases or conditions include cardiovascular disorders such as acute myocardial infarction; memory processes, dementia and cognition disorders such as Alzheimer""s disease and attention-deficit hyperactivity disorder; neurological disorders such as Parkinson""s disease, schizophrenia, depression, epilepsy, and seizures or convulsions; cancer such as cutaneous carcinoma, medullary thyroid carcinoma and melanoma; respiratory disorders such as asthma; sleep disorders such as narcolepsy; vestibular dysfunction such as Meniere""s disease; gastrointestinal disorders, inflammation, migraine, motion sickness, obesity, pain, and septic shock.
WO 00/06254 describes non-imidazole alkylamines as histamine-3 receptor ligands. EP 0 978 512 A1 describes non-imidazole aryloxy alkylamines as histamine-3 receptor ligands.
In its principle embodiment, the present invention discloses compounds of formula I: 
or a pharmaceutically acceptable salt thereof, wherein
Z is selected from the group consisting of a covalent bond and CH2;
R1 is selected from the group consisting of OR2, NR3R4 and 
R2 is selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, aminocarbonyl, sulfono and phosphono;
R3 and R4 are independently selected from the group consisting of hydrogen, alkenyl, alkenylcarbonyl, alkenyloxycarbonyl, alkenylsulfonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, alkynylcarbonyl, alkynyloxycarbonyl, alkynylsulfonyl, aminocarbonyl, aminosulfonyl, arylalkyl, arylalkenylcarbonyl, arylalkenylsulfonyl, arylalkylcarbonyl, arylalkylsulfonyl, arylarylcarbonyl, arylarylsulfonyl, arylcarbonyl, arylheterocylecarbonyl, arylheterocylesulfonyl, aryloxyarylcarbonyl, aryloxyarylsulfonyl, arylsulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkylcarbonyl, cycloalkylalkylsulfonyl, cycloalkylcarbonyl, cycloalkylsulfonyl, formyl, heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclealkylsulfonyl, heterocyclearylcarbonyl, heterocyclearylsulfonyl, heterocyclecarbonyl, heterocycleheterocyclecarbonyl, heterocycleheterocyclesulfonyl, heterocycleoxyalkylcarbonyl, heterocycleoxyarylcarbonyl, heterocycleoxyarylsulfonyl, heterocyclesulfonyl, and heterocyclethioalkylcarbonyl;
R5 and R6 are independently selected from the group consisting of hydrogen and alkyl;
R7 is selected from the group consisting of hydrogen and alkyl; or
R1 and R7 together form (xe2x95x90O);
R8 is selected from the group consisting of alkylcarbonyl, aryl, arylcarbonyl, arylcarbonylaryl, arylcarbonylheterocycle, cycloalkylcarbonyl, cycloalkylcarbonylaryl, cycloalkylcarbonylheterocycle, heterocycle, heterocyclecarbonyl, heterocyclecarbonylaryl, heterocyclecarbonylheterocycle; and
R9 is selected from the group consisting of hydrogen and lower alkyl.